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Novel Antinociceptive Agent against Persistent Pain

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 12298

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Special Issue Editor

Dr. Laura Micheli

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Guest Editor

Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy
Interests: pain pharmacology; chronic pain; inflammatory pain; chemotherapy induced neuropathic pain; trauma-induced neuropathic pain, glial cells; hyperalgesia; allodynia; in vivo approach; in vitro approach; therapeutic agents; pharmacological mechanism
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Special Issue Information

Dear Colleagues,

Effective pain therapy is one of society’s principal needs. Persistent and neuropathic pain represent a significant clinical problem and, as chronic conditions, can cause distress and seriously affect a patient’s quality of life. This condition is often refractory to conventional therapy. Analgesics that are used to treat different persistent pain conditions are usually marked by the onset of a several side-effects, and the great majority of patients obtain only partial relief. Therefore, the necessity of new analgesics is clear. Medicinal chemistry is continuously called to face the novel challenges that arise from the steady trickle of scientific breakthroughs to discover new, increasingly safe and effective drugs. This Special Issue of Molecules welcomes previously unpublished manuscripts covering all aspects of pharmacology and chemistry of antinociceptive drugs, in particular the development of novel pain-relieving molecules which are active against different persistent pain conditions.

Dr. Laura Micheli
Guest Editor

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Keywords

Chronic pain
Drug development
Glial cells
Inflammatory pain
Medicinal chemistry
Neuropathic pain
Pain
Pharmacodynamics
Visceral pain

Published Papers (4 papers)

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Research

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18 pages, 3867 KiB

Open AccessArticle

Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase

by Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Mir Mohammad Shahroz, Hemant Kumar Sharma, Yassine Riadi and Md Quamrul Hassan

Molecules 2021, 26(8), 2389; https://doi.org/10.3390/molecules26082389 - 20 Apr 2021

Cited by 9 | Viewed by 2613

Abstract

Ten benzoxazole clubbed 2-pyrrolidinones (11–20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11–20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO₂ derivative) and 20 (4-SO₂NH₂ derivative), with an IC₅₀ value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC₅₀ value above 50 µM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 Å) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively. Full article

(This article belongs to the Special Issue Novel Antinociceptive Agent against Persistent Pain)

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13 pages, 2271 KiB

Open AccessArticle

Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury

by Takahiro Kochi, Yoki Nakamura, Simeng Ma, Kazue Hisaoka-Nakashima, Dengli Wang, Keyue Liu, Hidenori Wake, Masahiro Nishibori, Masahiro Irifune and Norimitsu Morioka

Molecules 2021, 26(7), 2035; https://doi.org/10.3390/molecules26072035 - 2 Apr 2021

Cited by 17 | Viewed by 3694

Abstract

Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries. Full article

(This article belongs to the Special Issue Novel Antinociceptive Agent against Persistent Pain)

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16 pages, 4384 KiB

Open AccessArticle

Effect of Extract and Synthesized Derivatives of Isolated Compound from Symplocos chinensis f. Pilosa Ohwi on Neuropathic Pain in Mice

by Hyun-Yong Kim, Soo-Hyun Park, Guanglei Zuo, Kang Hyuk Kim, Seung Hwan Hwang, Hong-Won Suh and Soon-Sung Lim

Molecules 2021, 26(6), 1639; https://doi.org/10.3390/molecules26061639 - 15 Mar 2021

Cited by 3 | Viewed by 2317

Abstract

Neuropathic pain is described as the “most terrible of all tortures that a nerve wound may inflict.” The aim of the present study was to demonstrate the antinociceptive effect of Symplocos chinensis f. pilosa Ohwi water extract (SCW) and synthesized derivatives of the isolated compound. The antinociceptive effect was tested using the acetic acid-induced writhing and 5% formalin tests. Antinociceptive effects on neuropathic pain were evaluated using the von Frey test with chronic constriction injury (CCI) and surgical nerve injury (SNI) models and tail-flick test with a vincristine-induced pain model. An Ames test was also conducted. 5-hydroxymethylfurfural (5-HMF) was isolated and derivatives were synthesized with various acid groups. Among the plant water extracts, SCW showed significantly effective activity. Additionally, SCW presented antinociceptive effects in the neuropathic pain models. The SCW water fraction resulted in fewer writhes than the other fractions, and isolated 5-HMF was identified as an effective compound. Because 5-HMF revealed a positive response in the Ames test, derivatives were synthesized. Among the synthesized derivations, 5-succinoxymethylfurfural (5-SMF) showed the best effect in the neuropathic pain model. Our data suggest that SCW and the synthesized compound, 5-SMF, possess effective antinociceptive activity against neuropathic pain. Full article

(This article belongs to the Special Issue Novel Antinociceptive Agent against Persistent Pain)

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Review

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17 pages, 3873 KiB

Open AccessReview

LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

by Lorella Pasquinucci, Carmela Parenti, Zafiroula Georgoussi, Lorena Reina, Emilia Tomarchio and Rita Turnaturi

Molecules 2021, 26(14), 4168; https://doi.org/10.3390/molecules26144168 - 8 Jul 2021

Cited by 7 | Viewed by 2791

Abstract

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described. Full article

(This article belongs to the Special Issue Novel Antinociceptive Agent against Persistent Pain)

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